Monoclonal Antibody Pharmacokinetics and Structure

Study Notes

Monoclonal antibodies (mAbs) are used in drug development to treat various diseases including cancer, immunological disorders, and infectious diseases.
Over 60 antibodies are marketed in the US, with ~350 in development.
IgG subtype is most frequent, and abundantly explored therapeutically.
Mouse hybridoma technology introduced mAbs 40 years ago; using mouse mAbs had limitations due to immunogenicity, short half-life, and lack of effector function.
Chimeric and humanized antibodies are more common now. Phage display technology allows for fully human antibodies.
Humanized antibodies can also be generated from transgenic animals, human hybridomas, and patient-derived cells.

IgG is a Y-shaped immunoglobulin (150 kDa).
Two identical heavy chains and two identical light chains linked by disulfide bonds.
Two "arms" form the antigen-binding region (Fab), comprised of variable domains (heavy and light chain)
Fc region (stem) composed of only the heavy chains; FcyRs (IgG) receptor, complement system, and the FcRn important in therapeutic function.

mAbs typically have biphasic profiles: fast distribution phase, then slower elimination phase.
Distribution volume typically 3-8L, mostly confined to vascular and interstitial spaces.
mAbs are often administered intravenously or subcutaneously.

Oral bioavailability of mAbs is low (<1-2%).
Intravenous, subcutaneous, and occasionally intramuscular routes used clinically.
Key factors in bioavailability include blood flow, tissue morphology, biological interactions, and mAb properties.

Influenced by factors like target antigen binding affinity, internalization rate, tissue-specific features, and blood flow.
Low volume of distribution reflects restricted distribution.

mAbs are primarily eliminated via proteolytic degradation, resulting in smaller peptides and amino acids.
Nonspecific clearance via endocytosis and proteolysis in the liver/RE system is another route.
Target-mediated clearance plays a role; dependent on dose.
High molecular weight (150 kDa) prevents significant kidney clearance.

Immunogenicity refers to the body's immune response to the therapeutic protein.
Anti-drug antibodies (ADA) can form, affecting exposure, efficacy, and safety; potentially leading to accelerated mAb clearance.

Regulatory guidance and species relevance are essential factors.
Exposure-response relationships across species should be considered.
Non-Human Primates (NHP) are often the primary candidate due to close physiological similarity.

Bispecific antibodies are targeted to multiple antigens.
Antibody drug conjugates, glyco-engineered antibodies and novel scaffolds create unique challenges in applying quantitative pharmacology and translational PK/PD.
Bispecific antibodies (bsAbs) can target different pathways.